Bacterial pneumonia triggers an exuberant host response with excessive inflammation, oxidative stress, and epithelial cell damage culminating in ARDS. At present, therapeutic interventions to treat ARDS remain limited to lung-protective strategies, as newer molecular mechanism-driven therapeutic interventions have not yet emerged. The specific pathways involved in the evolution of epithelial damage remain elusive. In preliminary experiments, we discovered that a mitochondria-specific phospholipid, cardiolipin (CL), is a critical damage signal that produces severe epithelial lung injury. We observed that after bacterial infection of murine lung epithelial cells or mice, CL transmigrates from the inner to the outer mitochondrial membrane where it acts as a novel signal for autophagy of mitochondria, mitophagy. We also showed that bacterial infection induces cytochrome c (cyt c)-mediated CL peroxidation as a pivotal step in apoptosis. Thus peroxidation of externalized CL acts as a molecular switch that triggers the apoptotic machinery. Finally, we demonstrate that CL and oxidized CL (Clox) are released from injured host cells into circulation and act as mitochondria-derived damage associated molecular patterns (DAMP-CL) triggering innate and adaptive immune responses. Our central hypothesis is that bacterial infection stimulates the unmasking and release of mitochondrial Cls that are indispensible intracellular signals in accelerating mitophagy and apoptosis; upon release into circulation, Cls act as DAMP-CL inducing innate and adaptive immune responses. The Specific Aims of the proposed studies are to determine the: 1. Mechanisms and signaling role of CL asymmetry and its collapse in bacterial-induced mitophagy in distal lung epithelia. 2. Molecular pathways of CL peroxidation and the design and application of small-molecule regulators that protect against bacterial induced distal lung epithelial apoptosis. 3. Molecular identity of species of CUCLox as DAMP-CL in circulation. Based on the highly innovative concept that CL is a unique intra- and extra-cellular signal in mitophagy, apoptosis, and innate/adaptive immune responses in pulmonary epithelium, we will explore four new classes of regulators of CL signaling for the development of pulmonary protective drugs